In work that opens a new window on fighting cancer while minimizing side effects, researchers have developed the first small molecule that interacts with a cancer-cell-surface “death receptor,” an interaction that tells cancer cells to commit suicide.

The receptor, death receptor 5 (DR5), is rarely expressed on normal cells but is present on a variety of cancer cells, so activating it is likely to have few side effects on normal cells, although this hypothesis remains to be tested.

Cells are programmed to commit suicide, through a process known as apoptosis, when they are exposed to sufficiently stressful conditions. Cancer cells, however, have mechanisms that prevent apoptosis, helping them thrive even in the face of adversity.

For more than a decade, the drug discovery community has been trying to sidestep these protective mechanisms by directly targeting components of cancer cells’ mito­chondrial and cell-surface (“intrinsic” and “extrinsic”) apoptosis pathways. For example, scientists have identified small molecules that inhibit the anti-apoptosis protein Bcl-2, thereby activating the intrinsic apoptotic pathway. A few of these molecules are now in clinical trials for various cancers, although none has yet been approved.

Extrinsic activators of apoptosis could complement or exceed the capabilities of intrinsic ones. But efforts to come up with small-molecule activators of cancer cells’ extrinsic apoptotic pathway have been unsuccessful. The only extrinsic activators scientists have come up with are proteins that turn on four death receptors—TNFR1, Fas/CD95, DR4, and DR5. But proteins that activate TNFR1 and Fas/CD95 cause toxicity, and those that activate DR4 and DR5 disappear rapidly from the bloodstream or are only weakly effective.

The first small-molecule activators of death receptors raise hopes of overcoming such limitations. They were identified by a group led by Gelin Wang of the University of Texas, Dallas, Southwestern Medical Center and Xiaoguang Lei and Xiaodong Wang of the National Institute of Biological Sciences, Beijing (Nat. Chem. Biol., DOI: 10.1038/nchembio.1153).

The researchers screened a library of about 200,000 compounds to find agents that induce cell death in brain tumor cells. Structural analysis of these agents enabled the team to design a potent analog, which they call bioymifi. They found that bioymifi works by mimicking the ability of TRAIL, the natural DR5 ligand, to stimulate clustering of DR5, triggering apoptosis.

Genentech Senior Staff Scientist Avi Ashkenazi, whose lab discovered TRAIL and DR5, says the work by Wang, Lei, Wang, and colleagues “represents a significant breakthrough because it describes for the first time a direct small-molecule activator of the extrinsic pathway.”

Researchers could use small-molecule activators such as bioymifi to help investigate key drivers of efficacy in DR5 activation, he says, assuming the small-molecule agents turn out to be as free of side effects as large-molecule DR5 activators have proven to be.

Although it is currently unclear whether the small-molecule approach “will be advantageous over large-molecule strategies,” Ashkenazi adds, “it clearly has the potential to expand the pharmacological tool kit that is now available to harness the extrinsic pathway for therapeutic gain.” In addition, he says, bioymifi’s mechanism of action, stimulation of receptor clustering, is unique and surprising and could prove useful for activating other apoptosis receptors as well.